The search for novel agents in the prevention and treatment of prostate cancer continues. Agents capable to intervene simultaneously at several targets in the carcinogenic process will have selective advantage over other single-target agents. Recent studies have shown that monoterpenes possess anticancer properties and suggest that these compounds represent a new class of agents for cancer chemoprevention or therapy. Based on our recent exciting preliminary data and published studies there is a strong possibility that D-limonene, a monocyclic monoterpene, may be developed as novel chemopreventive and/or therapeutic agent. Because of the established role of Bcl2 and nuclear factor-kappaB (NF-kappaB) in regulating the transcription of a variety of genes involved during prostate carcinogenesis these two are important targets for prevention and therapy. The central hypothesis to be tested in this application is that D-limonene will impart cancer chemopreventive and/or therapeutic effects against prostate cancer by inhibiting NF-kB and Bcl2 expression in human prostate carcinoma cells. Under the proposed specific aims we will investigate the effect of D-limonene on constitutive- and TNFalpha- induced activation of NF-kappaB and Bcl2 family members and its proliferation in androgen-insensitive human prostate carcinoma cells. Further, we will study the effect of D-limonene on prostate carcinogenesis in TRAMP model expressing high basal levels of NF-kB and Bcl2 under androgen-dependent and -independent situations. Successful completion of this application will establish the cancer chemopreventive and/or therapeutic potential of D-limonene against prostate cancer and mechanisms involved with its anti-proliferative response.